Aina Hognestad

Interleukin-7–Mediated Inflammation in Unstable Angina Possible Role of Chemokines and Platelets

Background—Atherogenesis and plaque destabilization involve immune-mediated mechanisms, but the actual mediators have not been fully clarified. Interleukin (IL)-7 is a regulator of T-cell homeostasis but also may be involved in inflammation. We hypothesized that IL-7 could be involved in the inflammatory processes observed in atherosclerosis and acute coronary syndromes. Methods and Results—To study the role of IL-7 in coronary artery disease, we analyzed IL-7 levels and the effect of this cytokine on inflammatory mediators in patients with stable and unstable angina and in healthy control subjects. Our major findings were (1) Plasma levels of IL-7 were significantly increased in patients with stable (n=30) and unstable angina (n=30) comparing healthy control subjects (n=20), particularly in those with unstable disease. (2) Increased release from activated platelets appeared to be a major contributor to the raised IL-7 levels in patients with angina. (3) IL-7 enhanced the expression of several inflammatory chemokines in peripheral blood mononuclear cells from both healthy control subjects and patients with angina, particularly in those with unstable disease. Similar effects were seen in monocytes but not in T cells. (4) MIP-1&agr; further increased the release of IL-7 from platelets in a dose-dependent manner. (5) Aspirin reduced both the spontaneous and the SFLLRN-stimulated release of IL-7 from platelets, and when administered to healthy control subjects for 7 days (160 mg qd), it reduced plasma levels of IL-7. Conclusions—Our findings suggest a role for IL-7-driven inflammation in atherogenesis and the promotion of clinical instability in coronary artery disease involving interactions between platelets, monocytes, and chemokines.

Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.

OBJECTIVES This study was initiated to determine whether heart transplant recipients (HTRs) with cardiac allograft vasculopathy (CAV) have increased levels of high-sensitivity C-reactive protein (hsCRP) and to examine whether an increase in hsCRP after heart transplantation predicts the development of CAV. Furthermore, the effect of pravastatin on plasma levels of hsCRP in HTRs was investigated. BACKGROUND The relationship between CAV and hsCRP, as well as the effect of statins on hsCRP in HTRs, has not been well established. METHODS On referral for their annual angiographic control study, 150 consecutive HTRs (mean 6.5 years since transplantation) were included. Plasma levels of hsCRP were measured before angiography and compared with patients with (n = 52) and without (n = 98) CAV. In 49 of these patients, we additionally analyzed hsCRP in blood samples stored from their six-month visit after the transplantation procedure. Furthermore, in a randomized, crossover study, hsCRP was analyzed in 17 male HTRs before and after six weeks of treatment with 20 mg pravastatin. RESULTS Median levels of CRP were elevated among patients with CAV compared with those with normal angiograms [3.86 (1.78 to 7.00) vs. 1.08 (0.72 to 2.13) mg/l, p < 0.001]. Prospectively evaluated hsCRP levels from six months to follow-up were significantly higher among those who developed CAV compared with those with normal angiograms [+2.76 (1.56 to 5.00) vs. +0.07 (-0.57 to 0.41) mg/l, p < 0.001]. On multivariate analysis, the increase in hsCRP was the only significant predictor of CAV. Six weeks of treatment with pravastatin significantly reduced hsCRP levels by 25%, without any relation to changes in lipid values. CONCLUSIONS Elevated plasma levels of CRP are associated with angiographic evidence of CAV, and the increase in hsCRP is a strong predictor of development of CAV. Statin treatment reduces levels of hsCRP and should be used in HTRs, regardless of their lipid levels.

Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation

Background. N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. Methods. We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. Results. Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). Conclusions. In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

Platelet activation in heart transplant recipients

An inappropriate and persistent immune activation has been suggested to contribute to long-term mortality and morbidity after heart transplantation. Several lines of evidence suggest that platelets do not only promote thrombus formation, but also act as inflammatory cells. In the present study, we investigated if long-time survivors of heart transplantation (mean time since transplantation 6.5 yr) were characterized by enhanced platelet activation as assessed by different experimental approaches. Our main findings when comparing heart transplant recipients (n = 52) and age- and sex-matched healthy controls (n = 38) were: (i) platelets from heart transplant recipients showed enhanced expression of both P-selectin and CD63 as assessed by flow cytometry; (ii) platelets from these patients also contained significantly increased levels of soluble CD40 ligand and tended to release higher levels of this cytokine upon SFLLRN stimulation as assessed by enzyme immunoassay; (iii) heart transplant recipients had increased levels of soluble P-selectin in platelet-free plasma; and (iv) the enhanced platelet activation after heart transplantation was most pronounced in those with concomitant hypertension. These findings suggest that long-term survivors of heart transplantation are characterized by enhanced activation of platelets, possibly contributing to the persistent immune activation and clinical complications in these patients.